The present invention relates to substituted spiropiperidinyl derivatives that are useful in the pharmaceutical field. The compounds act as GPR120 receptor function regulating agents (modulators), which are useful as drugs for treating and/or preventing diabetes, obesity, hyperlipidemia, and inflammation related disorders.
GPR120, a G protein-coupled receptor, causes intracellular signaling through binding with unsaturated long chain fatty acids, such as alpha-linoleic acid, to induce various biological reactions. Actions of GPR120 and its ligand have been reported to promote secretion of glucagon-like-peptide-1 (“GLP-1”) functions to reduce blood glucose level in gastrointestinal cell lines. see Nature Medicine, 2005, 11(1), 90-94. GLP-1, which is a peptide hormone, has been found to induce insulin secretion depending on a blood glucose level. GLP-1 is also suggested to be efficacious for delaying the apoptosis of beta cells in type II diabetes mellitus.
GPR120 is expressed in adipocytes. GPR120 has been found to be increasingly expressed by adipose differentiation induction. In addition, actions of GPR120 and one of its putative ligand have been reported to suppress lipolysis in adipose-differentiated cells. A high blood lipid level is known to be one of the causes of insulin resistance. Suppression of lipolysis by a GPR120 agonist is thus expected to decrease the level of free fatty acid in blood to normalize a blood lipid level, resulting in improvement in insulin resistance.
GPR120 is also expressed in the pituitary gland, and a GPR120 ligand is reported to suppress adrenocorticotropic hormone secretion. Adrenocorticotropic hormone promotes glucocorticoid secretion downstream thereof to induce action such as promotion of glyconeogenesis in the liver, inhibitory action against glucose uptake in muscle and peripheral tissue, lipolysis in adipose tissue or release of fatty acid or glycerol. Accordingly, GPR120 is considered to exhibit hypoglycemic action or blood lipid lowering action via suppression action against adrenocorticotropic hormone secretion even in the central nervous system.
Recently, GPR120 has been shown to play a role in obesity in both mice and humans. GPR120 knockout mice fed a high fat diet developed obesity, glucose intolerance and fatty liver with decreased adipocyte differentiation and lipogenesis and enhanced hepatic lipogenesis. In the study, insulin resistance in such mice was associated with reduced insulin signaling and enhanced inflammation in adipose tissue. In human, GPR120 expression in adipose tissue is significantly higher in obese individuals than in lean controls. See Ichimura, et al., Nature, 2012, 483, 350-54; and Cintra, et al., Plos One, 2012, 7(1), 1-15.
GPR120 has also been shown to play a role in inflammation. Wild-type mice treated with omega-3 fatty acids inhibited macrophage-induced tissue inflammation and enhanced systemic insulin sensitivity. However, this effect was not observed in GPR120 knockout mice. See Oh, et al., Cell, 2010, 142, 687; and Talukar, et al., Trends in Pharmacological Sciences, 2011, 32(9), 543-550.
In light of the above description, a compound having GPR120 agonist activity is considered to be useful as an agent for treating and/or preventing diabetes mellitus, obesity, hyperlipidemia, and inflammation related disorders.